INFLUENCE OF TYPE AND NEUTRALISATION CAPACITY OF ANTACIDS ON DISSOLUTION RATE OF CIPROFLOXACIN AND MOXIFLOXACIN FROM TABLETS

Dissolution rate of two fl uoroquinolone antibiotics (ciprofl oxacin and moxifl oxacin) was analysed in presence/absence of three antacid formulations. Disintegration time and neutralisation capacity of antacid tablets were also checked. Variation in disintegration time indicated the importance of this parameter, and allowed evaluation of the infl uence of postponed antacid-fl uoroquinolone contact. Th e results obtained in this study showed decreased dissolution rate of fl uoroquinolone antibiotics from tablets in simultaneous presence of antacids, regardless of their type and neutralisation capacity.


Introduction
Fluoroquinolones (FQ) are broad spectrum antibacterial agents which chemically, may be regarded as weak substituted heterocyclic amino acids (). Fluoroquinolones are very effi cient against aerobic Gram-negative microorganisms but less effi cient against Gram-positive microorganisms (,). Th ese drugs are extremely useful for the treatment of a variety of infections, including urinary tract infections (), soft tissue infections (), respiratory infections (), bone-joint infections, typhoid fever, sexually transmitted diseases (), prostatitis (), community acquired pneumonia, acute bronchitis and sinusitis (). Also, a relatively new approach to the rational design of antitumour agents has been introduced based on some new quinolone molecules that display a novel mode of action (). Ciprofl oxacin and moxifl oxacin are members of fl uoroquinolone family which belong to third and fourth generation of these drugs, respectively (,, ). In clinical practice, fluoroquinolones are often administered concomitantly with other drugs which may contain metal ions. The presence of metal ions from e.g. metal based antacids may significantly affect the activity of quinolones since they can readily bind several divalent or trivalent metal ions (). Complexation alters solubility, lipophilicity, antimicrobial activity and protein binding capacity of quinolones. Solubility of all ionic quinolone complexes is much greater than that of molecular complexes which are only sparingly soluble ().
Some metal-quinolone complexes show antimicrobial activity comparable to that or free quinolone but in some cases the activity is increased or lowered. Mg + and Al + were found to decrease the activity of quinolones ().
Therefore, the aim of this study was to: √ determine disintegration time and neutralization capacity of tablets containing antacids, √ evaluate the infl uence of certain antacids on dissolution rate of fl uoroquinolones during simultaneous administration, √ determine dissolution rate of fl uoroquinolone formulations (ciprofl oxacin and moxifl oxacin tablets) tested alone or in combination with antacids, and on the basis of the results obtained evaluate the infl uence of antacids, concerning their neutralization capacity, on dissolution rate, √ evaluate the infl uence of postponed antacid-fl uoroquinolone contact in dissolution media on dissolution rate of ciprofl oxacin and moxifl oxacin tablets.

Reagents
The used reagents were all of analytical grade, unless otherwise stated. Ciprofloxacin hydrochloride monohydrate and moxifloxacin hydrochloride working standards were obtained from Merck (Darmstadt, Germany) and Bayer (Zürich, Switzerland), respectively. Hydrochloric acid  was obtained from by J.T. Baker (Deventer, Holland) and hydrochloric acid and sodium hydroxide titrimietric solutions (, mol/ dm  ) from Riedel-de Haën (Seelze-Hanover, Germany)

Disintegration testing
Th e following disintegration test was performed; in each of six tubes, one tablet is placed. Th e assembly was suspended in the  litre beaker, containing , mol/dm  HCl, and operated (without disks). A suitable device maintained temperature of the liquid at  o ±, o C. Th e test was provided using Pharma Test disintegration tester Type PTZ (Pharma Test, Hainburg, Germany).

Determination of neutralization capacity
Ten tablets containing antacid were weighed and the average tablet weight was determined. Th e tablets were ground to a fine powder, mixed to uniformity. The quantity of it, equivalent to the average tablet weight, was transferred to a  cm  beaker, diluted in  cm  of water and mixed on magnetic stirrer for two minutes ( rpm).  cm  of , mol/dm  HCl titrimietric solution (Riedel-de Haën, Seelze-Hanover, Germany) was added after mixing. After the addition of the acid the mixing procedure continued ( rpm), accurately timed, for  minutes. Excess hydrochloric acid was titrated with , mol/dm  NaOH titrimietric solution (Riedel-de Haën, Seelze-Hanover, Germany) to attain pH , stable for  seconds. The obtained result is expressed in mEq of acid neutralised/per tablet.

In vitro dissolution assay
The dissolution tests of ciprofloxacin and moxifloxa- Samples aliquots ( cm  ) were collected using graduated syringe after  minutes. Prior to use, the dissolution medium was equilibrated at  o C overnight to deareate medium. Th e suitability of the paddle apparatus was checked using the USP prednisone and salicylic acid calibrators -calibrators for system suitability test of basket and paddle dissolution apparatus (). One tablet of the corresponding quinolone (ciprofloxacin or moxifloxacin) was placed in each filled flask ( tablets per run) when establishing the dissolution profiles of quinolones in the absence of cations. These profiles were used to generate reference profi le. To evaluate the infl uence of the diff erent cations on the quinolone dissolution kinetics, the corresponding cation preparation was added to each flask at the same time as the quinolone formulation.
Absorbance versus concentration plots were linear over these concentration ranges and were used to determine percent of drug dissolved in the dissolution experiments.

Results and Discussion
Th e results of disintegration testing are summarised in Table , neutralisation capacity determination in Table  , and in vitro dissolution assay in Tables - (which show the amount of the dissolved drug-ciprofloxacin or moxifloxacin without/with antacid addition).
Values of dissolved moxifloxacin exceeding   are well within the deviation range for content uniformity allowed for solid preparations by both US and European Pharmacopoeias (±) (, ).

Conclusion
According to the results obtained in this study, we can conclude that dissolution rate of ciprofl oxacin and moxifl oxacin was downsized by simultaneous application of antacids. Th is infl uence was more pronounced in the case of ciprofl oxacin, than in the case of moxifl oxacin tablets. Also, similar relationship was found in decreased dissolution rate of ciprofl oxacin tablets compared to moxifl oxacin (, vs. ,) using the same antacids ("G" and " R"), under the same testing conditions. It can be assumed, that it is a consequence of similar mechanism of interaction which is not dependent of structural diff erences between ciprofl oxacin and moxifl oxacin. Regardless of the type and neutralization capacity of analysed antacids, which posses ability to chelate fl uoroquionolones, potential simultaneous application of these types of drugs (antacids and fl uoroquinolones) has appreciable infl uence on dissolution rate of ciprofl oxacin and moxifl oxacin tablets.
It was demonstrated in this study, that simultaneous application of antacids ("M", "G" and "R") with fluoroquinolones (ciprofloxacin and moxifloxacin) resulted in decreased dissolution rate (in wide range of concentrations, from -, to -,). Neutralisation capacity of antacids does not reflect their ability to form complexes with fluoroquinolones. Antacid with highest neutralisation capacity (, mEq acid/tablet) had minimal influence on dissolution rate of fluoroquinolone tablets (ciprofl oxacin tablets: -, ; moxifl oxacin tablets: -,). Disintegration time of antacid tablets has minor influence on drug quality and control. This parameter is very important in the analysis of other types of solid dosage forms. The main reason would be in the fact that antacid tablets are not swallowed, but gradually dissolved in oral cavity. Variation of disintegration time indicated the importance of this parameter, and allowed evaluation of the influence of postponed antacid-fluoroquinolone contact. In that manner, easy dissolution of tested fl uoroquinolones could be established (antacid tablets with disintegration time above two hours, caused minor decrease on dissolution rate of both fl uoroquinolones). Analysed antacids (two of three, "R" vs. "G"), disintegration time: "R" ≤  seconds, "G" ≤  minutes) with disintegration times signifi cantly shorter than dissolution testing period ( minutes) interacted fully with both fluoroquinolones and consequently resulted in decreased dissolution rate (ratio of relative decrease in dissolution rate with simultaneous addition of "R"/"G", was: ,/,=, times for ciprofloxacin tablets and ,/,=, times for moxifloxacin tablets.)